Over the past five years, we have developed and tested in vitro and in rive a panel of over twenty delta gamma1 34.5 herpes simplex viruses (HSV), genetically engineered to express a variety of different foreign gene inserts to enhance the oncolytic activity of the virus. We have successfully demonstrated that delta gamma1 34.5 HSV expressing IL-4 (R8306) or IL-12 (M002) significantly improved long-term survival in immunocompetent murine intracranial models of glioma and neuroblastoma, respectively. Replication competence, distribution and in vivo attributes of genetically engineered HSV have been extensively evaluated. Continued studies include the characterization of these delta gamma1 34.5 HSV that express cytokines capable of modulating the host immune response for in rive efficacy in a more relevant immunocompetent murine 4C8 glioma model, and the identification of effector mechanisms that mediate tumor cell killing. The proposed studies in this renewal application aim to identify the HSV genes whose modification enhances the cytoreductive capacity of our genetically engineered viruses without altering their safety. In Specific Aim 1, we will select viruses in rive with enhanced glioma eytoreductive effects and identify the responsible viral genes. Specific Aim 2 is to define the mechanism by which sequential administration of cytoreductive viruses interact with tumor cells and to improve the oncolytic response on sequential administration of genetically engineered viruses in rive. Finally, studies outlined in Specific Aim 3 will investigate the potential effects of recombinant viruses between wild-type and genetically engineered HSV carrying foreign gene inserts.